The following (template) letter is being sent to all IND-holders of antiretrovirals in the development for HIV.  The purpose is to encourage sponsors to study their drug in patient populations with limited treatment options, and to collaborate with other drug sponsors to develop therapeutic options.  The letter clarifies the agency's position on combining investigational drugs in clinical trials, and designing trials that include treatment experienced populations.  This letter was drafted in response to discussions held with respresentatives of several community groups, at the "Salvage Workshop" in Toronto, Canada, in May 1999

IND Number

XXX Pharmaceuticals, Inc.
Attn:

Dear XXX:

Please refer to your investigational new drug (IND), submitted under 505(i) of the Federal Food, Drug, and Cosmetic Act for (drug name).

The purpose of this correspondence is to encourage all sponsors with antiretroviral drugs in development to conduct studies in treatment-experienced HIV-infected individuals and to promote pharmaceutical collaboration to meet this objective.  As you are aware, accelerated approval regulations (21 CFR 314.500) provide an approval mechanism for products used to treat serious and life-threatening illnesses that represent improvements over available therapy, or treatments for individuals who have exhausted existing options.   Thus, it is expected that most new drug applications for antiretrovirals submitted under the accelerated approval mechanism will include some clinical data in patients with limited treatment options.

Scientific data clearly support the principle that HIV should be treated with combination therapy to maintain durable virologic suppression.  Whenever possible, all trial participants should have the opportunity to receive combination therapy with several potentially active drugs.  Therefore, in studies involving patients with limited approved treatment options, combining multiple investigational agents may be necessary.  We would like to clarify that neither the Division of Antiviral Drug Products (DAVDP) nor the regulations prohibit the use of more than one investigational agent in a clinical trial or expanded access program.  In fact, DAVDP encourages the study and/or treatment use of multiple investigational agents as appropriate for patients with limited treatment options.

However, when including multiple investigational drugs in phase 3 pivotal trials, the division recommends that the study design be such that the contribution of the investigational agent(s) of interest can be distinguished.  We fell that this can be reasonably accomplished through "factorial" comparisons.  The division will also accept other design proposals in which investigational drug activity and safety can be isolated.  Study design and statistical methods for analyzing such studies should be discussed with the division in advance.  In addition, potential drug-drug interactions among investigational agents should be sufficiently understood prior to initiation of a large study to avoid inappropriate dosing or safety risks due to overlapping toxicities.

We would be happy to discuss any new protocol proposals for the study of heavily pretreated patients with (drug name ) in combination with other approved or investigational drugs and would be appreciative of pharmaceutical collaboration in the development of innovative trial designs in the study of this patient population.

If you have any questions, please contact (FDA contact), Regulatory Project Manager at 301-827-2335.

Sincerely yours,

/s/
Heidi Jolson, M.D., M.P.H.
Director
Division of Antiviral Drug Products
Office of Drug Evaluation IV
Center for Drug Evaluation and Research

Posted on Web by:
Office of Special Health Issues
Office of International and Constituent Relations
September 30, 1999

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